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  • A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.

A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (2014-02-05)
Habibul Ahsan, Jerry Halpern, Muhammad G Kibriya, Brandon L Pierce, Lin Tong, Eric Gamazon, Valerie McGuire, Anna Felberg, Jianxin Shi, Farzana Jasmine, Shantanu Roy, Rachelle Brutus, Maria Argos, Stephanie Melkonian, Jenny Chang-Claude, Irene Andrulis, John L Hopper, Esther M John, Kathi Malone, Giske Ursin, Marilie D Gammon, Duncan C Thomas, Daniela Seminara, Graham Casey, Julia A Knight, Melissa C Southey, Graham G Giles, Regina M Santella, Eunjung Lee, David Conti, David Duggan, Steve Gallinger, Robert Haile, Mark Jenkins, Noralane M Lindor, Polly Newcomb, Kyriaki Michailidou, Carmel Apicella, Daniel J Park, Julian Peto, Olivia Fletcher, Isabel dos Santos Silva, Mark Lathrop, David J Hunter, Stephen J Chanock, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Magdalena Lochmann, Lars Beckmann, Rebecca Hein, Enes Makalic, Daniel F Schmidt, Quang Minh Bui, Jennifer Stone, Dieter Flesch-Janys, Norbert Dahmen, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Kamila Czene, Astrid Irwanto, Jianjun Liu, Nazneen Rahman, Clare Turnbull, Alison M Dunning, Paul Pharoah, Quinten Waisfisz, Hanne Meijers-Heijboer, Andre G Uitterlinden, Fernando Rivadeneira, Dan Nicolae, Douglas F Easton, Nancy J Cox, Alice S Whittemore
PMID24493630
ABSTRACT

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.